The long-term goal is to pursue an academic career as an independent investigator, clinical consultant and teacher. The applicant plans to develop specific expertise in the area of the control of the pulmonary circulation, focusing on the role of vasoactive substances in the mediation of pulmonary vascular tone and pulmonary transvascular exchange of water and protein. This study will investigate the role of vaso-active substances in both human and animal models of pulmonary hypertension. Studies of the metabolic activities of the lung indicate that several mediator systems interact to produce net circulatory effects, especially in pathophysiologic states. Thus, the study of the interrelationships between the renin-angiotensin, kallikrein-kinin and catecholamine systems and the arachidonate cascade is a principal focus of this proposal since each of these systems is known to be vasoactive in the pulmonary circulation. Models of altered pulmonary function in chronically-instrumented, unanesthetized sheep and newborn lambs will include acute, chronic and repeated intermittent hypoxia (with and without hypercarbia) and pulmonary hypertention in the newborn (induced by intrauterine hypoxia). The specific aims are: 1. To examine the effects of changes in gas tension (PaO2, PaCO2, pH) on the endogenous activity of these mediator systems; 2. To relate these induced changes in mediator concentrations to changes in pulmonary and systemic hemodynamics (electromagnetic flow probe and thermodilution methods), pulmonary transvascular exchange of water and protein (endogenous proteins in lung lymph and plasma using electroimmunoassay), gas exchange (alveolar to arterial oxygen gradient) and distribution of cardiac output (microsphere mehod); 3. To use selective pharmacologic blockers and inhibitors to establish the relative contributions of these mediator systems to the observed ciculatory changes. Studies will be performed in patients with idiopathic pulmonary hypertension in the newborn (persistence of the fetal circulation) or older child, and pulmonary hypertension secondary to congenital heart defects or respiratory disorders. By focusing on the interactions between these vasoactive mediator systems, these studies will provide new insights into the pathogenesis of pulmonary hypertension and pulmonary edema, and suggest new approachs to pharmacologic intervention.